Breast and prostate cancers are leading causes of morbidity and mortality caused by a combination of inherited and environmental factors. For the vast majority of these cases, we do not understand the underlying causes, or why different groups have higher rates (e.g. prostate cancer in African Americans). We propose to identify genetic factors that contribute to these cancers by performing well-powered genome-wide association studies, informed by environmental and lifestyle histories collected prospectively in the Multiethnic Cohort (MEC) of African Americans, Latinos, Japanese Americans, Native Hawaiians and Whites n Los Angeles, California and Hawaii. In the previous grant cycle, we established a large repository of DNA and serum and investigated common genetic variation in candidate gene pathways for breast, prostate and colorectal cancer, We developed methods to test genetic variation for association with cancer risk, that now serve as models for the NCI Cohort Consortium and others. In the current cycle, we propose to perform whole-genome association scans of breast and prostate cancer using a two-stage design to identify pan- ethnic genetic variants that affect risk in all five racial-ethnic populations. In stage 1 we will genotype 550,000 single nucleotide polymorphisms (SNPs) in 2,000 breast and 2,000 prostate cancer cases and 4,000 controls. In stage 2 we will perform follow-up genotyping of 4,600 SNPs for each cancer to replicate initial associations in similar numbers of cases and controls. Using the combined stage 1+2 dataset, we will examine interaction between these SNPs and environmental factors and disease severity. These studies will also be designed to identify variants that display strong effects in specific racial-ethnic groups and serve as the initial stage for whole-genome scans in non-White populations. We will also develop a public data enclave to allow access by other investigators to this data. In addition, we propose to establish a population- based repository of tumor specimens from breast and prostate cancer cases in these racial-ethnic groups to be utilized in future studies as relevant molecular classifiers are defined by the Cancer Genome Project. We expect this work to significantly advance knowledge of the etiology of these cancers across these racial- ethnic populations, guiding the development of future preventive, early detection, prognostic and even therapeutic measures.